Tetrahydroquinoline derivatives

ABSTRACT

The present invention relates to tetrahydroquinoline derivatives having general formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is formyl, (1-6C)alkylcarbonyl or (1-6C)alkylsulfonyl; R2 and R3 are H or (1-4C)alkyl; R4 is phenyl; R5 is (1-4C)alkyl; Y—X is (CO)—O, (SO)2—O, NHC(O)—O, NHC(S)—O, OC(O)—O, bond-O, C(O)—NH, S(O)2—NH, NHC(O)—NH, NHC(S)—NH, OC(O)—NH, bond-NH, NH—C(O), O—C(O), NH—S(O)2, or O—S(O)2 or Y—X is a bond; R6 is H, trifluormethyl, (1-6C)alkyl, 1- or 2-adamantyl(1-4C)alkyl, (2-6C)alkenyl, (3-9C)heteroaryl, (3-6C)cycloalkyl, (2-6C)heterocycloalkyl, (1-4C)alkylthio(1-4C)alkyl, (6-10C)aryl(1-4C)alkyl, (3-9C)heteroaryl(1-4C)alkyl, (3-6C)cycloalkyl(1-4C)alkyl, (2-6C)heterocycloalkyl(1-4C)alkyl, R8,R9-aminocarbonyl(1-4C)alkyl, R8,R9-amino(1-4C)alkyl, R8-oxycarbonyl(1-4C)alkyl, R8-oxy(1-4C)alkyl, R8-carbonyl(1-4C)alkyl or (6-10C)aryl; R7 is H, (1-4C)alkyl, (1-4C)alkoxy, halogen, trifluoromethyl, cyano, nitro hydroxyl; and R8 and/or R9 is H, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (6-10C)aryl, (3-9C)heteroaryl, (6-10C)aryl(1-4C)alkyl, (3-9C)heteroaryl(1-4C)alkyl, (3-6C)cycloalkyl(1-4C)alkyl, (2-6C)heterocycloalkyl(1-4C)alkyl, (1-4C)(di)alkylamino(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylthio(1-4C)alkyl, (1-4C)alkylcarbonylamino(1-4C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl, (1-4C)alkoxycarbonylamino(1-4C)alkyl, (3-6C)cycloalkyl, (2-6C)heterocycloylkyl, or R8 and R9 may be joined in a (2-6C)heterocycloalkyl ring. The present invention also relates to pharmaceutical compositions comprising said derivatives and the use of these derivatives to control fertility.

The invention relates to a compound having FSH modulatory activity, inparticular a tetrahydroquinoline derivative, to a pharmaceuticalcomposition containing the same, as well as the use of said compound inmedical therapy.

Gonadotropins serve important functions in a variety of bodily functionsincluding metabolism, temperature regulation and the reproductiveprocess. Gonadotropins act on specific gonadal cell types to initiateovarian and testicular differentiation and steroidogenesis. Thehypophyseal gonadotropin FSH (follicle stimulating hormone) for exampleplays a pivotal role in the stimulation of follicle development andmaturation whereas LH (luteinizing hormone) induces ovulation (Sharp, R.M. Clin Endocrinol. 33:787-807, 1990; Dorrington and Armstrong, RecentProg. Horm. Res. 35:301-342, 1979). Currently, FSH is appliedclinically, in combination with LH, for ovarian stimulation i.e. ovarianhyperstimulation for in vitro fertilisation (IVF) and induction ofovulation in infertile anovulatory women (Insler, V., Int. J. Fertility33:85-97, 1988, Navot and Rosenwaks, J. Vitro Fert. Embryo Transfer5:3-13, 1988), as well as for male hypogonadism and male infertility.

The gonadotropin FSH is released from the anterior pituitary under theinfluence of gonadotropin-releasing hormone and oestrogens, and from theplacenta during pregnancy. In the female, FSH acts on the ovariespromoting development of follicles and is the major hormone regulatingsecretion of oestrogens. In the male, FSH is responsible for theintegrity of the seminiferous tubules and acts on Sertoli cells tosupport gametogenesis. Purified FSH is used clinically to treatinfertility in females and for some types of failure of spermatogenesisin males. Gonadotropins destined for therapeutic purposes can beisolated from human urine sources and are of low purity (Morse et al,Amer. J. Reproduct. Immunol. and Microbiology 17:143, 1988).Alternatively, they can be prepared as recombinant gonadotropins.Recombinant human FSH is available commercially and is being used inassisted reproduction (Olijve et al. Mol. Hum. Reprod. 2:371, 1996;Devroey et al. Lancet 339:1170, 1992).

The actions of the FSH hormone are mediated by a specific plasmamembrane receptor that is a member of the large family of G-proteincoupled receptors. These receptors consist of a single polypeptide withseven transmembrane domains and are able to interact with the Gsprotein, leading to the activation of adenylate cyclase.

The FSH receptor is a highly specific target in the ovarian folliclegrowth process and is exclusively expressed in the ovary. Blocking thisreceptor or inhibiting the signaling which is normally induced afterFSH-mediated receptor activation will disturb follicle development andthus ovulation and fertility. Low molecular weight FSH antagonists couldtherefore form the basis for new contraceptives. Such FSH antagonistscould give rise to diminished follicle development (no ovulation) withstill sufficient estrogen production left to avoid adverse effects one.g. bone mass.

The present invention describes the preparation of low molecular weighthormone analogs that selectively have modulatory activity on the FSHreceptor. The compounds of the invention can either be used as partial)agonists or (partial) antagonists of the FSH-receptor.

Thus, it has now been found, that the following class oftetrahydroquinoline compounds of formula I or pharmaceuticallyacceptable salts thereof, have FSH-modulatory activity:

wherein

-   -   R¹ is formyl, (1-6C)alkylcarbonyl or (1-6C)alkylsulfonyl;    -   R² and R³ are H or (1-4C)alkyl;    -   R⁴ is phenyl, optionally substituted with one or more        substituents selected from the group hydroxy, amino, halogen,        nitro, trifluoromethyl, cyano, (1-4C)alkyl, (2-4C)alkenyl,        (2-4C)alkynyl, (1-4C)alkoxy, (1-4C)(di)alkylamino. Preferable        position of substitution is the para-position.    -   R⁵ is (1-4C)alkyl;    -   Y—X is C(O)—O, S(O)₂—O, NHC(O)—O, NHC(S)—O, OC(O)—O, bond-O,        C(O)—NH, S(O)₂—NH, NHC(O)—NH, NHC(S)—NH, OC(O)—NH, bond-NH,        NH—C(O), O—C(O), NH—S(O)₂, or O—S(O)₂ or X—Y is a bond;    -   R⁶ is H, trifluoromethyl, (1-6C)alkyl, 1- or        2-adamantyl(1-4C)alkyl, (2-6C)alkenyl, (2-6C)alkenyl,        (6-10C)aryl, (3-9C)heteroaryl, (3-6C)cycloalkyl,        (2-6C)heterocycloalkyl, (1-4C)alkylthio(1-4C)alkyl,        (6-10C)aryl(1-4C)alkyl, (3-9C)heteroaryl(1-4C)alkyl,        (3-6C)cycloalkyl(1-4C)alkyl, (2-6C)heterocycloalkyl(1-4C)alkyl,        R⁸,R⁹-aminocarbonyl(1-4C)alkyl, R⁸,R⁹-amino(1-4C)alkyl,        R⁸-oxycarbonyl(1-4C)alkyl, R⁸-oxy(1-4C)alkyl,        R⁸-carbonyl(1-4C)alkyl;

If R⁶ is H, it is to be noted that X—Y may not be a bond.

If R⁶ is phenyl, phenyl may, in addition to the substituents for(6-10C)aryl groups as mentioned in the definitions, optionally besubstituted with (6-10C)aryl, (6-10C)aryloxy, (6-10C)aryl(1-4C)alkoxy,(3-9C)heteroaryl, (3-9C)heteroaryloxy, (3-9C)heteroaryl(1-4C)alkoxy,(1-4C)alkylcarbonylamino, (1-4C)alkylcarbonyloxy,(3-6C)cycloalkylcarbonyloxy,(1-4C)alkoxycarbonyl(1-4C)alklylcarbonyloxy,(1-4C)alkoxy(1-4C)alkylcarbonyloxy, (6-10C)arylcarbonyloxy,(3-9C)heteroarylcarbonyloxy, (1-4C)alkylsulfonyloxy,(6-10C)arylsulfonyloxy, (3-9C)heteroarylsulfonyloxy,(1-4C)(di)alkylcarbamoyl, (6-10C)(di)arylcarbamoyl,(2-6C)heterocycloalkylcarbamoyl, (6-10C)(di)arylamino, (3-6C)cycloalkyl,(3-6C)cycloalkyl(1-4C)alkyl, (2-6C)heterocycloalkyl,(2-6)heterocycloalkyl(1-4C)alkyl.

R⁷ is H, (1-4C)alkyl, (1-4C)alkoxy, halogen, trifluoromethyl, cyano,nitro, hydroxyl; R⁸ and/or R⁹ is H, (1-4C)alkyl, (2-4C)alkenyl,(2-4C)alkynyl, (6-10C)aryl, (3-9C)heteroaryl, (6-10C)aryl(1-4C)alkyl,(3-9C)heteroaryl(1-4C)alkyl, (3-6C)cycloalkyl(1-4C)alkyl,(2-6C)heterocycloalkyl(1-4C)alkyl, (1-4C)(di)alkylamino(1-4C)alkyl,(1-4C)alkoxy(1-4C)alkyl, (1-4C)alkylthio(1-4C)alkyl,(1-4C)alkylcarbonylamino(1-4C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,(1-4C)alkoxycarbonylamino(1-4C)alkyl, (3-6C)cycloalkyl,(2-6C)heterocycloalkyl, or R⁸ and R⁹ may be joined in a(2-6C)heterocycloalkyl ring.

The compounds according to the present invention modulate the FSHreceptor function and can be used for the same clinical purposes asnative FSH if they behave like agonists, with the advantage that theydisplay altered stability properties and may be administereddifferently. If they block the FSH receptor they can be used e.g. as acontraceptive agent.

Thus, the FSH-receptor modulators of the present invention may be usedfor treating infertility, for contraception and for treatment ofhormone-dependent disorders such as breast cancer, prostate cancer, andendometriosis. Preferably the compounds of the present invention areused to inactivate the FSH-receptor.

The term (1-4C)alkyl as used in the definition means a branched orunbranched alkyl group having 1-4 carbon atoms, for example methyl,ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

The term (1-6C)alkyl as used in the definition means a branched orunbranched alkyl group having 1-6 carbon atoms, for example methyl,ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and hexyl.(1-5C)Alkyl groups are preferred, (1-4C)alkyl being the most preferred.

The term 1- or 2-adamantyl(1-4C)alkyl means an adamantyl group attachedat position 1 or 2 to an alkyl group containing 1-4 carbon atoms, withthe same meaning as previously defined.

The term (2-4C)alkenyl means a branched or unbranched alkenyl grouphaving 2-4 carbon atoms, such as ethenyl and 2-butenyl.

The term (2-6C)alkenyl means a branched or unbranched alkenyl grouphaving 2-6 carbon atoms, such as ethenyl, 2-butenyl, and n-pentenyl.

The term (2-4C)alkynyl means a branched or unbranched alkynyl grouphaving 2-4 carbon atoms, such as ethynyl and propynyl.

The term (2-6C)alkyl means a branched or unbranched alkynyl group having2-6 carbon atoms, such as ethynyl, propynyl and n-pentynyl.

The term (3-6C)cycloalkyl means a cycloalkyl group having 3-6 carbonatoms, being cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term (2-6C)heterocycloalkyl means a heterocycloalkyl group having2-6 carbon atoms, preferably 3-5 carbon atoms, and at least includingone heteroatom selected from N, O and/or S, which may be attached via aheteroatom if feasible, or a carbon atom. Preferred heteroatoms are N orO. Most preferred are piperidine, morpholine and pyrrolidine.

The term (1-4C)alkoxy means an alkoxy group having 1-4 carbon atoms, thealkyl moiety having the same meaning as previously defined. (1-2C)Alkoxygroups are preferred.

The term (6-10C)aryl means an aromatic hydrocarbon group having 6-10carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl or indenyl,which may optionally be substituted with one or more substituentsselected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano,(1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxy,(1-4C)(di)alkylamino, the alkyl moieties having the same meaning aspreviously defined. The preferred aromatic hydrocarbon group is phenyl.

The term (3-9C)heteroaryl means a substituted or unsubstituted aromaticgroup having 3-9 carbon atoms, at least including one heteroatomselected from N, O and/or S, like imidazolyl, thiadiazolyl, pyridyl,(benz)thienyl, (benzo)furyl, quinolyl, tetrahydroquinolyl, quinoxalyl orindolyl. The substituents on the heteroaryl group may be selected fromthe group of substituents listed for the aryl group. The heteroarylgroup may be attached via a carbon atom or a heteroatom, if feasible.Preferred heteroaryl groups are thienyl, furyl and pyridyl.

The term (6-10C)aryloxy means an aryl group containing 6-10 carbon atomsas defined previously, attached to an oxygen atom. (3-9C)Heteroaryloxygroups are analogs of the (6-10C)aryloxy groups, at least including oneheteroatom selected from N, O or S.

The term (1-4C)alkoxycarbonyl(1-4C)alkyl means an alkoxycarbonylalkylgroup, wherein the alkoxy group contains 1-4 carbon atoms with the samemeaning as previously defined and the alkyl group contains 1-4 carbonatoms with the same meaning as previously defined.

The term (1-4C)alkoxy(1-4C)alkyl means an alkoxyalkyl group, wherein thealkoxy group contains 1-4 carbon atoms with the same meaning aspreviously defined and the alkyl group contains 1-4 carbon atoms withthe same meaning as previously defined.

The term (3-6C)cycloalkyl(1-4C)alkyl means a cycloalkyl group of 3-6carbon atoms attached to an alkyl group of 1-4 carbon atoms, wherein thecycloalkyl group is a (3-6C)cycloalkyl group as previously defined andthe alkyl group is a (1-4C)alkyl group as previously defined.

The term (2-6C)heterocycloalkyl(1-4C)alkyl means a heterocycloalkylgroup of 2-6 carbon atoms attached to an alkyl group of 1-4 carbonatoms, wherein the heterocycloalkyl group is a (2-6C)heterocycloalkylgroup as previously defined and the alkyl group is a (1-4C)alkyl groupas previously defined.

The term (1-4C)(di)alkylamino means a (di)alkylamino group, the alkylgroups of which contain 1-4 carbon atoms and have the same meaning aspreviously defined.

The term (6-10C)(di)arylamino means a (di)arylamino group, the arylgroups of which contain 6-10 carbon atoms and have the same meaning aspreviously defined.

The term (1-4C)(di)alkylamino(1-4C)alkyl means a (di)alkylaminoalkylgroup, the alkyl groups of which contain 1-4 carbon atoms and have thesame meaning as previously defined.

The term (1-4C)alkylthio(1-4C)alkyl means an alkylthioalkyl group, thealkyl groups of which contain 1 to 4 carbon atoms and have the samemeaning as defined previously.

The term aminocarbonyl(1-4C)alkyl in the definition ofR⁸,R⁹-aminocarbonyl(1-4C)alkyl means an aminocarbonylalkyl group, thealkyl group of which contains 1-4 carbon atoms and has the same meaningas previously defined. The aminocarbonylmethyl group is the preferredaminocarbonylalkyl group.

The term amino(1-4C)alkyl in the definition of R⁸,R⁹-amino(1-4C)alkylmeans an aminoalkyl group, the alkyl group of which contains 1-4 carbonatoms and has the same meaning as previously defined.

The term oxycarbonyl(1-4C)alkyl in the definition ofR⁸-oxycarbonyl(1-4C)alkyl means an oxycarbonylalkyl group, the alkylgroup of which contains 1-4 carbon atoms and has the same meaning aspreviously defined. The oxycarbonylmethyl group is the preferredoxycarbonylalkyl group.

The term oxy(1-4C)alkyl in the definition of R⁸-oxy(1-4C)alkyl means anoxyalkyl group, the alkyl group of which contains 1-4 carbon atoms andhas the same meaning as previously defined.

The term carbonyl(1-4C)alkyl in the definition of R⁸-carbonyl(1-4C)alkylmeans a carbonylalkyl group, the alkyl group of which contains 1-4carbon atoms and has the same meaning as previously defined.

The term (6-10C)aryl(1-4C)alkyl means an arylalkyl group having 7-14carbon atoms, wherein the alkyl group is a (1-4C)alkyl group and thearyl group is a (6-10C)aryl as previously defined. Phenyl(1-4C)alkylgroups are preferred arylalkyl groups, such as benzyl.(3-9C)Heteroaryl(1-4C)alkyl groups are analogs of the(6-10C)aryl(1-4C)alkyl groups, at least including one heteroatomselected from N, O and/or S, the heteroaryl group of which may beattached via a carbon atom or via a heteroatom if feasible.

The term joined in a (2-6C)heterocycloalkyl ring in the definition ofNR⁸R⁹, where R⁸ and R⁹ together with the nitrogen atom to which they areattached form a ring, means a ring containing the nitrogen atom andfurther having at most 2-6 carbon atoms, which ring may contain one ormore additional heteroatoms selected from N, O and/or S. Examples ofsuch rings are azetidine, pyrrolidine, piperidine, piperazine, and(thio)morpholine.

The term halogen means fluorine, chlorine, bromine or iodine.

The term (1-6C)alkylcarbonyl means an alkylcarbonyl group, the alkylgroup of which contains 1-6 carbon atoms and has the same meaning aspreviously defined. (1-4C)Alkylcarbonyl groups are preferred.

The term (1-4C)alkylcarbonylamino(1-4C)alkyl means analkylcarbonylaminoalkyl group, the alkyl groups of which contain 1-4carbon atoms and have the same meaning as previously defined.

The term (6-10C)aryl(1-4C)alkoxy means an aryl group containing 6-10carbon atoms as defined previously, attached to an (1-4C)alkoxy group asdefined previously. (3-9C)Heteroaryl(1-4C)alkoxy groups are analogs ofthe (6-10C)aryl(1-4C)alkoxy groups, at least including one heteroatomselected from N, O or S, the heteroaryl group of which may be attachedvia a carbon atom or via a heteroatom, if feasible.

The term (1-4C)alkylcarbonyloxy means an alkylcarbonyloxy group thealkyl group of which contains 1-4 carbon atoms. The term(3-6C)cycloalkylcarbonyloxy means a cycloalkylcarbonyloxy group thecycloalkyl group of which contains 3-6 carbon atoms, the cycloalkylmoiety of which has the same meaning as previously defined.

The term (1-4C)alkoxycarbonyl(1-4C)alkylcarbonyloxy means an(1-4C)alkoxycarbonyl group attached to an alkylcarbonyloxy group thealkyl moiety of which contains 1-4 carbon atoms, the alkoxy group ofwhich has the same meaning as previously defined.

The term (1-4C)alkoxy(1-4C)alkylcarbonyloxy means an alkoxy group with1-4 carbon atoms attached to an alkylcarbonyloxy group with 1-4 carbonatoms, the alkoxy and alkyl groups having the same meaning as previouslydefined.

The term (1-4C)alkylcarbonylamino means an alkylcarbonylamino group thealkyl group of which contains 1-4 carbon atoms.

The term (1-4C)alkoxycarbonylamino(1-4C)alkyl means an alkoxycarbonylgroup containing 1-4 carbon atoms with the same meaning as previouslydefined, attached to an aminoalkyl group, the alkyl group of whichcontains 1-4 carbon atoms with the same meaning as previously defined.

The term (6-10C)arylcarbonyloxy means an arylcarbonyloxy group the arylgroup of which contains 6-10 carbon atoms. Preferred arylcarbonyloxygroup is a phenylcarbonyloxy group. (3-9C)Heteroarylcarbonyloxy groupsare analogs of the (6-10C)arylcarbonyloxy groups, at least including oneheteroatom selected from N, O or S and may be attached via a carbon atomor a heteroatom, if feasible.

The term (1-4C)alkylsulfonyl means an alkylsulfonyl group, the alkylgroup of which contains 1-4 carbon atoms and has the same meaning aspreviously defined.

The term (1-6C)alkylsulfonyl means an alkylsulfonyl group, the alkylgroup of which contains 1-6 carbon atoms and has the same meaning aspreviously defined. (1-3C)Alkylsulfonyl groups are preferred.

The term (1-4C)alkylsulfonyloxy means an alkylsulfonyloxy group, thealkyl group of which contains 1-4 carbon atoms and has the same meaningas previously defined. (1-3C)Alkylsulfonyloxy groups are preferred.

The term (6-10C)arylsulfonyloxy means an arylsulfonyloxy group, the arylgroup of which contains 6-10 carbon atoms and has the same meaning aspreviously defined. The phenylsulfonyloxy group is preferred.(3-9C)Heteroarylsulfonyloxy groups are analogs of the(6-10C)arylsulfonyloxy groups, at least including one heteroatomselected from N, O or S, which may be attached via a carbon atom or aheteroatom, if feasible.

The term (1-4C)(di)alkylcarbamoyl means a (di)alkylcarbamoyl group, thealkyl groups of which contain 1-4 carbon atoms and have the same meaningas previously defined.

The term (6-10C)(di)arylcarbamoyl means a (di)arylcarbamoyl group, thearyl moieties of which contains 6-10 carbon atoms and have the samemeaning as previously defined.

The term (2-6C)heterocycloalkylcarbamoyl means aheterocycloalkylcarbamoyl group, the heterocycloalkyl group of whichcontains 2-6 carbon atoms and has the same meaning as previouslydefined.

Preferred compounds of the invention are compounds of formula I, whereinY—X is C(O)—NH, OC(O)—NH, or C(O)—O. More preferred are compoundswherein Y—X is C(O)—NH.

Further preferred are compounds wherein R¹ is (1-4C)alkylcarbonyl,preferably acetyl and/or R² and/or R³ and R⁵ are independently(1-4C)alkyl, more preferably methyl.

R⁶ preferably is a bulky group. Preferred compounds are those wherein R⁶is (6-10C)aryl, (3-9C)heteroaryl, (6-10C)aryl(1-4C)alkyl or(3-9C)heteroaryl(1-4C)alkyl. Most preferred are compounds wherein R⁶ is(6-10C)aryl, even more preferred phenyl. The preferred R⁷ group is H,(1-4C)alkyl or (1-4C)alkoxy. Most preferred are H or (1-4C)alkyl, evenmore preferred H or methyl. Most preferred are compounds wherein R⁷ isH.

In the most preferred compounds according to the invention R¹ is(1-4C)alkylcarbonyl, R², R³, R⁵ are independently (1-4C)alkyl, R⁴ isphenyl and Y—X is C(O)—NH and R⁷ is H. Even more preferred are compoundswherein R¹ is acetyl, R², R³, R⁵ are independently methyl, R⁴ is phenyland Y—X is C(O)—NH and R⁷ is H.

In the above-mentioned preferred compounds substitutions are allowed asindicated in the definitions of the groups. Phenyl in R⁶ can in additionbe substituted as indicated in the definition for R⁶.

Excluded from the invention are the compounds1-acetyl-6-benzoylamino-4-(4-methylphenyl)-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline,1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4,6-tetramethylquinoline,1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4,6,8-pentamethylquinoline,1-acetyl-6-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline,1-acetyl-6-trifluoroacetylamino-4-(4-methylphenyl)-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline,1-acetyl-6-trifluoroacetylamino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline,1-acetyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,4,6-tetramethylquinolineand1-acetyl-4-(4-bromophenyl)-1,2,3,4-tetrahydro-2,2,4,6-tetramethylquinoline.

The disclaimer relates to the disclosures in Ref Zh., Khim. Abstr. No.1Zh311, 1972; Khim. Geterosikl. Soedin. 7:795, 1971; Ambinter ScreeningCollection, order nrs 28020-A0839/0039328 (CAS 310456-97-4) and-A0705/0032919 (CAS 327981-38-4); ChemDiv. Inc. order nr 8005-9747(CAS360760-14-1); ChemStar Product list, order nr CHS0065413 (CAS299418-67-0); Asinex Compound Collection, order nr BAS0068990 (CAS299970-20-0).

Suitable methods for the preparation of the compounds of the inventionare outlined below.

The compounds of the present invention in which R² and R³ are methyl canbe prepared starting from (protected) anilines of general formula II-a-ein which R⁷ has the same meaning as previously defined, by means of thewell-documented Skraup reaction, which yields1,2-dihydro-2,2,4-trimethylquinoline derivatives of formula III-a-e.

Related Skraup cyclizations are found in literature: A. Knoevenagel,Chem. Ber. 54:1726, 1921; R. L. Atkins and D. E. Bliss, J. Org. Chem.43:1975, 1978; J. V. Johnson, B. S. Rauckman, D. P. Baccanari and B.Roth, J. Med. Chem. 32:1942, 1989; W. C. Lin, S.-T. Huang and S.-T. Lin,J. Chin. Chem. Soc. 43:497, 1996; J. P. Edwards, S. J. West, K. B.Marschke, D. E. Mais, M. M. Gottardis and T. K. Jones, J. Med. Chem.41:303, 1998.

The abovementioned reaction is typically conducted at elevatedtemperature in acetone, mesityl oxide or ethylacetoacetate in thepresence of iodine or protic acid such as hydrochloric acid,p-toluenesulfonic acid or aqueous hydrogen iodide. Alternatively,1,2-dihydro-2,2,4-trimethylquinolines of formula III-a-e can be preparedby reacting the corresponding aniline of formula II-a-e with acetone inthe presence of MgSO₄, 4-tert-butylcatechol and iodine (L. G. Hamann, R.I. Higuchi, L. Zhi, J. P. Edwards and X.-N. Wang, J. Med. Chem, 41:623,1998). Starting materials can be either obtained directly fromcommercial sources or prepared by art-known aromatic ring substitutions,as are described e.g. by H. Cerfontain, Y. Zou and B. H. Bakker, Recl.Trav. Chim. Pays-Bas, 113:403, 1994; A. Coppock, J. Org. Chem. 22:325,1957; M. Schlosser, J. H. Choi and S. Takagishi, Tetrahedron, 46:5633,1990.

Alternatively, compounds of general structure VI-a-e, in which R² and R³are (2-4C)alkyl and R⁷ is as previously defined, can generally besynthesized by cyclization of an aniline of formula IV-a-e with anappropriate ketone of formula V.

The abovementioned reaction is typically conducted in an inert solventsuch as toluene, at elevated temperature using protic or Lewis acidssuch as, but not limited to, p-toluenesulfonic acid or borontrifluorideto promote the cyclization (H. Walter, H. Sauter and T. Winkler, Helv.Chim. Acta, 75:1274, 1992; H. Walter, Helv. Chim. Acta, 77; 608, 1994;H. Walter and J. Schneider, Heterocycles, 41:1251, 1995; J. P. Edwards,J. D. Ringgenberg and T. K. Jones, Tetrahedron Lett. 39:5139, 1998).

The requisite building blocks of formula IV-a-e may be prepared byWittig reaction of ketones of formula VII-a-e. Introduction ofsubstituents A on the aromatic ring can be accomplished using art-knownaromatic ring substitutions either in the aniline stage or in the1,2-dihydro-2,2,4-trimethylquinoline stage, as was mentioned above forcompounds of formula II.

In another approach, compounds of formula VI-a-e in which R²═R³═H can beprepared from anilines of general formula II-a-e by reaction with1-methylstyrene and formaldehyde in acetonitrile at ambient or elevatedtemperature. Related cyclizations are described in literature: J. M.Mellor and G. D. Merriman, Tetrahedron, 51:6115, 1995.

Subsequent 1-N-acylation or 1-N-sulfonylation of compounds of formula VIwherein R², R³, R⁷ and A are as previously defined, can be carried outusing standard conditions, well known to those skilled in the art. In atypical experiment, compounds of formula VI are reacted in a solventsuch as dichloromethane, tetrahydrofuran, toluene or pyridine with anacylhalide or acid anhydride or a sulfonylchloride in the presence of abase such as, but not limited to, N,N-diisopropylethylamine,triethylamine, piperidine or sodium hydride to give N-acylated orN-sulfonylated 1,2-dihydro-4-methylquinoline derivatives of formulaVIII-a and VIII-b, respectively.

Related N-acylations of a dihydroquinoline scaffold are found inliterature: Zh. V. Shmyreva, Kh. S. Shikhaliev and E. B. Shpanig, Izv.Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol. 31:45, 1988; Zh. V.Shmyreva, Kh. S. Shikhaliev, L. P. Zalukaev, Y. A. Ivanov, Y. S.Ryabokobylko and I. E. Pokrovskaya, Zh. Obshch. Khim. 59:1391, 1989.

1-N-Formylation can be readily established by reaction ofdihydroquinoline of formula VI with formic acid in the presence oftrifluoroacetic acid at elevated temperature (see for example P.Bouyssou, C. Le Goff and J. Chenault, J. Heterocycl. Chem. 29:895, 1992)or with formic acid ethyl ester in the presence of sodium acetate, aswas described in literature by e.g. N. Atanes, S. Perez, E. Guitan, L.Castedo and J. M. Saa, Tetrahedron, 50:11257, 1994.

Introduction of the requisite phenyl group at position 4 of thedihydroquinoline scaffold can be accomplished via Friedel-Craftsalkylation of (substituted) benzene derivatives with the compounds ofgeneral structure VIII, wherein R¹, R², R³, R⁷ and A are as previouslydefined.

The latter reaction is typically conducted at elevated temperatureseither in neat (substituted) benzene or in an appropriate inert solventsuch as heptane or hexane with (substituted) benzene as reagent, undercatalysis of a Lewis acid (e.g. AlCl₃, AlBr₃, FeCl₃ or SnCl₄).Friedel-Crafts alkylations with 1,2-dihydro-2,2,4-trimethylquinolinesare described in literature by B. A. Lugovik, L. G. Yudin and A. N.Kost, Dokl. Akad. Nauk SSSR, 170:340, 1966; B. A. Lugovik, L. G. Yudin,S. M. Vinogradova and A. N. Kost, Khim. Geterosikl. Soedin, 7:795, 1971.

Compounds of the present invention, wherein R⁵≠Me and R¹, R², R³, R⁴, R⁷and A are as previously defined, represented by formula XII, may besynthesized starting from tetrahydroquinoline ketones of formula X.Thus, Wittig reaction of a ketone of formula X with the appropriateWittig reagent yields the unsaturated derivative represented by formulaXI, which in turn is the starting material for a Friedel-Craftsalkylation of (substituted) benzene, via the same procedure as wasoutlined above for the preparation of compounds with general structureIX.

The abovementioned Wittig reaction is well known to those skilled in theart.

The requisite ketone of formula X can be prepared by reaction of ananiline of formula II with 3-chloro-3-methyl-1-butyne (XIII) indiethylether/water in the presence of copper powder and triethylaminewhich yields an alkyne of formula XIV. Hydrogen-halogen exchange can becarried out by deprotonation of a compound of formula XIV in an inertsolvent such as tetrahydrofuran with n-butyllithium at temperaturesbelow −50° C. upon addition of p-toluenesulfonylchloride to give achloride of general formula XV. Finally, acid-catalyzed (e.g. sulfuricacid) cyclization can be carried out at elevated temperature in asolvent such as polyethyleneglycol to give compounds of formula XVI,which can be acylated or sulfonylated as was previously described forderivatives of general formula VI.

The abovementioned reaction sequence is described in literature: P.Barmettler and H.-J. Hansen, Helv. Chim. Acta, 73:1515, 1990 (andreferences cited in there).

Functionalization of position 6 in tetrahydroquinolines of generalstructure XII can be accomplished via art-known deprotection-couplingprocedures:

Compounds of the present invention wherein X═O and Y═C(O), S(O)₂,NHC(O), NHC(S), OC(O) or a bond, represented by formula I-a, can beprepared from 6-methoxy-containing tetrahydroquinoline of formula XII-a.Demethylation is well known to those skilled in the art.

In a typical experiment, demethylation is achieved upon reaction of acompound of formula XII-a with BBr₃ in an inert solvent such as, but notlimited to, dichloromethane or tetrahydrofuran at low temperature togive deprotected compounds of general formula XVII. Alternatively,demethylation can be accomplished upon reaction of compounds of formulaXII-a with BF₃Me₂S complex at ambient temperature in an inert solvent aswas mentioned for demethylations using BBr₃.

Subsequent functionalizations of the free OH group in derivatives offormula XVII are also well known to those skilled in the art and can beeasily established using reagents of formula XVIII-a-g.

For the halide-containing reagents of formula XVIII, the abovementionedreaction is typically conducted at room temperature in a suitablesolvent, e.g. an aprotic solvent such as N,N-dimethylformamide,dichloromethane or tetrahydrofuran, in the presence of a base, such as,but not limited to, N,N-diisopropylethylamine or sodium hydride.Additives such as N,N-dimethylaminopyridine or tetrabutylammoniumiodidemay accelerate the latter reaction. Furthermore, utilisation ofisocyanates or isothiocyanates of formula XVIII-d and XVIII-e in aninert solvent at ambient or elevated temperatures yields compounds offormula I-a wherein Y═NHC(O) or NHC(S), respectively.

Compounds wherein Y═C(O) may also be obtained in an alternative wayusing carboxylic acids of general formula XVIII-b, using a couplingreagent such as O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) or bromotripyrrolodinophosphoniumhexafluorophosphate (PyBrOP) and a tertiary base, e.g.N,N-diisopropylethylamine, in a solvent such as N,N-dimethylformamide ordichloromethane at ambient or elevated temperature.

Compounds represented by formula I-b-c, in which W═R⁸, R⁹N or R⁸O,respectively, can be synthesized by reacting compounds of generalformula XVII with an acid chloride of formula XIX using standardconditions.

Alternatively, compounds of structure I-b-c may be prepared fromderivatives of formula XVII and an acid chloride of formula XIX in whichW═OEt, followed by base-mediated (e.g NaOH) saponification andsubsequent condensation of the free carboxylic acid with either aminesof general structure R⁸, R⁹NH or alcohols of general structure R⁸OH inthe presence of a coupling reagent such as the earlier mentioned TBTU,HATU or PyBrOP and a tertiary base such as N,N-diisopropylethylamine.

Compounds represented by formula I-d-e, in which V═R⁸, R⁹N or R⁸O,respectively, can be obtained via nucleophilic substitution of a halogensuch as Br, present in compounds of formula XXI by amines of generalstructure R⁸, R⁹NH or alcohols of general structure R⁸OH. In turn, therequisite tetrahydroquinoline of formula XXI can be synthesized from acompound of formula XVII and a bromoacylchloride of general structureXX, using art-known synthetic procedures.

Compounds represented by formula I-f-g, in which U=(substituted)heteroaromatic or (substituted) phenyl, respectively, may be preparedvia Suzuki coupling of (substituted) iodobenzoylderivatives of formulaXXII with boronic acids of general formula XXII-a-b.

In a typical experiment, an iodide of formula XXII is reacted with aboronic acid of formula XXII-a-b in a solvent mixture such asdimethoxyethane/ethanol using cesium fluoride and a palladium catalystsuch as palladiumtetrakistriphenylphosphine ortris(dibenzylideneacetone)dipalladium at elevated temperature under anitrogen atmosphere. Addition of triphenylphosphine may accelerate thereaction and improve the yield. The abovementioned reaction is describedextensively in literature. See for example: A. Suzuki, Acc. Chem. Res.15:178, 1982; N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Satohand A. Suzuki, J. Am. Chem. Soc. 111:314, 1989.

Likewise, compounds represented by formula I-h wherein X═NH and Y is aspreviously defined can be synthesized via the same methods as weredescribed above for compounds of general formula Ia-g in which X═O.

Compounds represented by formula I-i-j in which X═C(O) or S(O)₂ and Y═NHor O, respectively, may be obtained via reaction of the correspondingacyl or sulfonyl chlorides of formula XXV with amines of generalstructure R⁶NH₂ or alcohols of general structure R⁶OH via the samemethod as was described earlier for the preparation of compounds offormula I-a.

The requisite acyl or sulfonyl chlorides of formula XXV can be preparedfrom the corresponding compounds of formula XXIV by treatment with e.gPOCl₃, PCl₅, oxalylchloride, phosgene or SOCl₂, in solvents such astoluene, acetonitrile, or N,N-dimethylformamide, as is describedextensively in literature. See for example M. Bonnat, M. Bradley and J.D. Kilburn, Tetrahedron Lett. 37:5409, 1996; J. G. Montana, G. M.Buckley, N. Cooper, H. J. Dyke and L. Gowers, Bioorg. Med. Chem. Lett,8:2635, 1998; J. Hayler, P. D. Kane, D. LeGrand, F. Lugrin, K. Menear,R. Price, M. Allen, X. Cockcroft, J. Ambler, K. Butler and K. Durren,Bioorg. Med. Chem. Lett. 10:1567, 2000.

Alternatively, compounds of formula XXIV in which X═C(O) can be useddirectly as starting materials for the preparation of derivatives offormula I-i-j, using coupling reagents as were mentioned previously.

For compounds represented by formula I-k-p, wherein X═C(O) or S(O)₂ andY═NH or O and n=1-4, art-known synthetic procedures can be followed.

Thus, preparation of tetrahydroquinolines of formula I-k-l can beaccomplished by condensing an amine or alcohol represented by formulaXXVI (Y═NH or O, respectively) with chlorides of general formula XXVusing standard conditions. In a similar approach, amines or alcohols offormula XXVII can be utilized to prepare compounds of formula I-m-n.Finally, the use of the earlier mentioned boronic acids XXIII leads tothe preparation of compounds of formula I-o-p via the earlier mentionedSuzuki coupling reaction.

Compounds of the present invention wherein X—Y is a bond, represented byformula I-q, can be prepared directly from commercially available oreasily preparable anilines of formula XXVIII via the reaction sequenceSkraup, acylation and Friedel-Crafts alkylation.

In another approach, compounds represented by formula I-r in which X—Yis a bond and U=(substituted) heteroaromatic or (substituted) phenyl,may be prepared via Suzuki condensation of the corresponding 6-iodotetrahydroquinoline derivatives of formula XXIX with boronic acids ofgeneral formula XXIII, as was previously mentioned.

The requisite iodide of formula XXIX can be obtained from thecorresponding amine by means of the well-known Sandmeijer reaction.

Some of the compounds of the invention, which can be in the form of afree base, may be isolated from the reaction mixture in the form of apharmaceutically acceptable salt. The pharmaceutically acceptable saltsmay also be obtained by treating the free base of formula I with anorganic or inorganic acid such as hydrogen chloride, hydrogen bromide,hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionicacid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid,fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid,and ascorbic acid.

The compounds of the present invention possess at least one chiralcarbon atom and may therefore be obtained as pure enantiomers, or as amixture of enantiomers, or as a mixture of diastereomers. Methods forobtaining the pure enantiomers are well known in the art, e.gcrystallization of salts which are obtained from optically active acidsand the racemic mixture, or chromatography using chiral columns. Fordiastereomers, straight phase or reversed phase columns may be used.

The compounds of the invention may form hydrates or solvates. It isknown to those of skill in the art that charged compounds form hydratedspecies when lyophilized with water, or form solvated species whenconcentrated in a solution with an appropriate organic solvent. Thecompounds of this invention include the hydrates or solvates of thecompounds listed.

For selecting active compounds testing at 10⁻⁵ M must result in anactivity of more than 20% of the maximal activity when FSH is used as areference. Another criterion might be the EC₅₀ value which must be <10⁻⁵M, preferably <10⁻⁷ M.

The skilled artisan will recognize that desirable EC₅₀ values aredependent on the compound tested. For example, a compound with an EC₅₀which is less than 10⁻⁵ M is generally considered a candidate for drugselection. Preferably this value is lower than 10⁻⁷ M. However, acompound which has a higher EC₅₀, but is selective for the particularreceptor, may be even a better candidate.

Methods to determine receptor binding, as well as in vitro and in vivoassays to determine biological activity, of gonadotropins are wellknown. In general, expressed receptor is contacted with the compound tobe tested and binding or stimulation or inhibition of a functionalresponse is measured.

To measure a functional response, isolated DNA encoding the FSH receptorgene, preferably the human receptor, is expressed in suitable hostcells. Such a cell might be the Chinese Hamster Ovary cell, but othercells are also suitable. Preferably the cells are of mammalian origin(Jia et al, Mol. Endocrin., 5:759-776, 1991).

Methods to construct recombinant FSH expressing cell lines are wellknown in the art (Sambrook et al., Molecular Cloning: a LaboratoryManual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, latestedition). Expression of receptor is attained by expression of the DNAencoding the desired protein. Techniques for site directed mutagenesis,ligation of additional sequences, PCR, and construction of suitableexpression systems are all, by now, well known in the art. Portions, orall, of the DNA encoding the desired protein can be constructedsynthetically using standard solid phase techniques, preferably toinclude restriction sites for ease of ligation. Suitable controlelements for transcription and translation of the included codingsequence can be provided to the DNA coding sequences. As is well known,expression systems are now available which are compatible with a widevariety of hosts, including prokaryotic hosts such as bacteria andeukaryotic hosts such as yeast, plant cells, insect cells, mammaliancells, avian cells and the like.

Cells expressing the receptor are then contacted with the test compoundto observe binding, or stimulation or inhibition of a functionalresponse.

Alternatively, isolated cell membranes containing the expressed receptormay be used to measure binding of compound.

For measurement of binding, radioactively labeled or fluorescentlylabeled compounds may be used. As reference compound human recombinantFSH can be used. In the alternative also competition binding assays canbe performed.

Another assay involves screening for FSH receptor agonist compounds bydetermining stimulation of receptor mediated cAMP accumulation. Thus,such a method involves expression of the receptor on the cell surface ofa host cell and exposing the cell to the test compound. The amount ofcAMP is then measured. The level of cAMP will be reduced or increased,depending on the inhibitory or stimulating effect of the test compoundupon binding to the receptor.

In addition to direct measurement of e.g. cAMP levels in the exposedcell, cells lines can be used which in addition to transfection withreceptor encoding DNA are also transfected with a second DNA encoding areporter gene the expression of which responds to the level of cAMP.Such reporter genes might be cAMP inducible or might be constructed insuch a way that they are connected to novel cAMP responsive elements. Ingeneral, reporter gene expression might be controlled by any responseelement reacting to changing levels of cAMP. Suitable reporter genes aree.g. LacZ, alkaline phosphatase, firefly luciferase and greenfluorescence protein. The principles of such transactivation assays arewell known in the art and are described e.g. in Stratowa, Ch., Himmler,A. and Czernilofsky, A. P., (1995) Curr. Opin. Biotechnol. 6:574.

The present invention also relates to a pharmaceutical compositioncomprising a tetrahydroquinoline derivative or pharmaceuticallyacceptable salts thereof having the general formula I in admixture withpharmaceutically acceptable auxiliaries and optionally other therapeuticagents. The auxiliaries must be “acceptable” in the sense of beingcompatible with the other ingredients of the composition and notdeleterious to the recipients thereof. The pharmaceutical compositionsmay also comprise the tetrahydroquinoline derivatives1-acetyl-6-benzoylamino-4-(4-methylphenyl)-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline,1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4,6-tetramethylquinoline,1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4,6,8-pentamethylquinoline,1-acetyl-6-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline,1-acetyl-6-trifluoroacetylamino-4-(4-methylphenyl)-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline,1-acetyl-6-trifluoroacetylamino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline,1-acetyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,4,6-tetramethylquinolineand1-acetyl-4-(4-bromophenyl)-1,2,3,4-tetrahydro-2,2,4,6-tetramethylquinoline.

Compositions include e.g. those suitable for oral, sublingual,subcutaneous, intravenous, intramuscular, local, or rectaladministration, and the like, all in unit dosage forms foradministration.

For oral administration, the active ingredient may be presented asdiscrete units, such as tablets, capsules, powders, granulates,solutions, suspensions, and the like.

For parenteral administration, the pharmaceutical composition of theinvention may be presented in unit-dose or multi-dose containers, e.g.injection liquids in predetermined amounts, for example in sealed vialsand ampoules, and may also be stored in a freeze dried (lyophilized)condition requiring only the addition of sterile liquid carrier, e.g.water, prior to use.

Mixed with such pharmaceutically acceptable auxiliaries, e.g. asdescribed in the standard reference, Gennaro, A. R. et al., Remington:The Science and Practice of Pharmacy (20th Edition., Lippincott Williams& Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing),the active agent may be compressed into solid dosage units, such aspills, tablets, or be processed into capsules or suppositories. By meansof pharmaceutically acceptable liquids the active agent can be appliedas a fluid composition, e.g. as an injection preparation, in the form ofa solution, suspension, emulsion, or as a spray, e.g. a nasal spray.

For making solid dosage units, the use of conventional additives such asfillers, colorants, polymeric binders and the like is contemplated. Ingeneral any pharmaceutically acceptable additive which does notinterfere with the function of the active compounds can be used.Suitable carriers with which the active agent of the invention can beadministered as solid compositions include lactose, starch, cellulosederivatives and the like, or mixtures thereof, used in suitable amounts.For parenteral administration, aqueous suspensions, isotonic salinesolutions and sterile injectable solutions may be used, containingpharmaceutically acceptable dispersing agents and/or wetting agents,such as propylene glycol or butylene glycol.

The invention further includes a pharmaceutical composition, ashereinbefore described, in combination with packaging material suitablefor said composition, said packaging material including instructions forthe use of the composition for the use as hereinbefore described.

The tetrahydroquinoline derivatives of the invention can also beadministered in the form of implantable pharmaceutical devices,consisting of a core of active material, encased by a releaserate-regulating membrane. Such implants are to be applied subcutaneouslyor locally, and will release the active ingredient at an approximatelyconstant rate over relatively large periods of time, for instance fromweeks to years. Methods for the preparation of implantablepharmaceutical devices as such are known in the art, for example asdescribed in European Patent 0,303,306 (AKZO Nobel N. V.).

The exact dose and regimen of administration of the active ingredient,or a pharmaceutical composition thereof, will necessarily be dependentupon the therapeutic effect to be achieved (treatment of infertility;contraception), and may vary with the particular compound, the route ofadministration, and the age and condition of the individual subject towhom the medicament is to be administered.

In general parenteral administration requires lower dosages than othermethods of administration which are more dependent upon absorption.However, a dosage for humans preferably contains 0.0001-25 mg per kgbody weight. The desired dose may be presented as one dose or asmultiple subdoses administered at appropriate intervals throughout theday, or, in case of female recipients, as doses to be administered atappropriate daily intervals throughout the menstrual cycle. The dosageas well as the regimen of administration may differ between a female anda male recipient.

Thus, the compounds according to the invention can be used in therapy.

A further aspect of the invention resides in the use of atetrahydroquinoline derivative compound having the general formula I forthe manufacture of a medicament to be used for the treatment ofdisorders responsive to FSH receptor mediated pathways, preferably forthe control of fertility, more preferably for the treatment ofinfertility or to prevent fertility. The compounds according to theinvention can also be used for the treatment of hormone-dependentdisorders such as breast cancer, prostate cancer and endometriosis.

The invention is illustrated by the following examples.

EXAMPLES Example 11-Acetyl-6-(tert-butoxycarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a). 6-(tert-Butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline

A mixture of N-Boc-1,4-phenylenediamine (5.0 g) and iodine (1.3 g) inmesityl oxide (25 ml) was stirred at 100° C. for 2 h. The reactionmixture was concentrated in vacuo and the residue was chromatographed onAl₂O₃ (Alumina B, act. III) in heptane/dichloromethane=8/2 as eluent.

Yield: 2.9 g. MS-ESI: [M+H]⁺=289.2

(b).1-Acetyl-6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline

Acetyl chloride (11.1 ml) and acetic anhydride (11.1 ml) were addeddropwise to a solution of6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (8.5g) in pyridine (22 ml) and dichloromethane (212 ml). After stirring for18 h, the reaction mixture was washed with 2 M HCl and water. Theorganic layer was dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was chromatographed on silicagel in heptane/ethyl acetate=8/2(v/v) as eluent.

Yield: 6.7 g. MS-ESI: [M+H]⁺=331.2

(c).1-Acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

A mixture of1-acetyl-6-(tert-butoxycarbonyl)amino-2,2,4-trimethyl-1,2-dihydroquinoline(2.4 g) and AlCl₃ (9.5 g) in benzene (150 ml) was stirred at 70° C. for1 h. The reaction mixture was cooled (0° C.) and quenched with water andin addition a solution of 2 M NaOH was added. The organic layer wasseparated, dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was chromatographed on silicagel in heptane/ethyl acetate=8/2(v/v) as eluent.

Yield: 1.6 g. MS-ESI: [M+H]⁺=309.2

(d).1-Acetyl-6-(tert-butoxycarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

A mixture of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(20 mg), (Boc)₂O (30 mg) and N,N-diisopropylethylamine (20 μl) intetrahydrofuran (4 ml) was stirred at 60° C. for 18 h. The reactionmixture was concentrated in vacuo and the residue was chromatographed onsilicagel in dichloromethane/methanol=1/0=>95/5 (v/v) as eluent.

Yield: 8 mg. MS-ESI: [M+H]⁺=409.2

Example 26-Amino-1-butyryl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a).6-(tert-Butoxycarbonyl)amino-1-butyryl-1,2-dihydro-2,2,4-trimethylquinoline

Butyryl chloride (185 μl) was added dropwise to a solution of6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (50mg) and a catalytic amount of N,N-dimethylaminopyridine in pyridine (4ml). After stirring for 18 h, the reaction mixture was concentrated invacuo. The residue was dissolved in ethyl acetate and washed with water.The organic layer was separated, dried (MgSO₄) and concentrated invacuo. The residue was chromatographed on silicagel in heptane/ethylacetate=1/0=>7/3 (v/v) as eluent.

Yield: 47 mg. MS-ESI: [M+H]⁺=359.4

(b).6-Amino-1-butyryl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

A mixture of1-butyryl-6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline(47 mg) and AlCl₃ (52 mg) in benzene (2 ml) was stirred at 60° C. for 6h. The reaction mixture was cooled (0° C.) and quenched with water andin addition a solution of 2 M NaOH was added. The organic layer wasseparated, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by preperative HPLC.

Yield: 10 mg. MS-ESI: [M+H]⁺=337.2; HPLC: R_(t)=6.97 min. (method 1)

Example 31-Acetyl-6-amino(4-chlorophenyl)-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

A mixture of1-acetyl-6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline(25 mg) and AlCl₃ (35 mg) in chlorobenzene (2 ml) was stirred for 1 h.The reaction mixture was quenched with water and in addition a solutionof 2 M NaOH and ethyl acetate were added. The organic layer wasseparated, dried over MgSO₄ and concentrated in vacuo.

Yield: 20 mg. MS-ESI: [M+H]⁺=343.4; HPLC: R_(t)=6.16 min. (method 1)

Example 41-Acetyl-6-amino-4-(4-fluorophenyl)-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Friedel-Crafts alkylation of fluorobenzene (2 ml) with1-acetyl-6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline(25 mg) in the presence of AlCl₃ (35 mg) was performed according to themethod described in example 3.

Yield: 15 mg. MS-ESI: [M+H]⁺=327.4; HPLC: R_(t)=5.63 min. (method 1)

Example 51-Acetyl-6-amino-1,2,3,4-tetrahydro-4-(4-toloyl)-2,2,4-trimethylquinoline

Friedel-Crafts alkylation of toluene (2 ml) with1-acetyl-6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline(25 mg) in the presence of AlCl₃ (35 mg) was performed according to themethod described in example 3.

Yield: 22 mg. MS-ESI: [M+H]⁺=323.2

Example 61-Acetyl-6-(4-chlorobenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

A mixture of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg), 4-chlorobenzoyl chloride (11 mg) and N,N-diisopropylethylamine(22 μl) in tetrahydrofuran (1 ml) was stirred for 18 h. The reactionmixture was concentrated in vacuo, the residue was dissolved in ethylacetate and washed with 0.5HCl, water, 5% aq. NaHCO₃, water and brine.The organic layer was separated, dried (MgSO₄) and concentrated invacuo. The residue was chromatographed on silicagel in heptane/ethylacetate=1/0=>0/1 (v/v) as eluent.

Yield: 9.5 mg. MS-ESI: [M+H]⁺=447.4; HPLC: R_(t)=10.87 min. (method 1)

Example 71-Acetyl-6-benzoylamino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with benzoyl chloride (9.1 mg) and N,N-diisopropylethylamine (22μl) in tetrahydrofuran (1 ml) was performed according to the methoddescribed in example 6.

Yield: 1.2 mg. MS-ESI: [M+H]⁺=413.4; HPLC: R_(t)=10.01 min. (method 1)

Example 81-Acetyl-4-phenyl-1,2,3,4-tetrahydro-6-(4-[trifluoromethyl]benzoyl)amino-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 4-trifluoromethylbenzoyl chloride (14 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 6.

Yield: 8.9 mg. MS-ESI: [M+H]⁺=481.4; HPLC: R_(t)=10.76 min. (method 1)

Example 91-Acetyl-6-(4-nitrobenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 4-nitrobenzoyl chloride (12 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 6.

Yield: 8.2 mg. MS-ESI: [M+H]⁺=458.4; HPLC: R_(t)=10.02 min. (method 1)

Example 101-Acetyl-4-phenyl-6-(4-n-propylbenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 4-n-propylbenzoyl chloride (12 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 6.

Yield: 6.7 mg. MS-ESI: [M+H]⁺=455.4; HPLC: R_(t)=11.19 min. (method 1)

Example 111-Acetyl-6-(3-bromo-2,6-dimethoxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

A mixture of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(25 mg), 3-bromo-2,6-dimethoxybenzoic acid (23 mg),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (68 mg) and N,N-diisopropylethylamine (32 μl)in dichloromethane (4 ml) was stirred for 18 h. The reaction mixture wasconcentrated in vacuo, the residue was dissolved in ethyl acetate andwashed with 0.5 M HCl, water, 5% aq. NaHCO₃, water and brine. Theorganic layer was dried (MgSO₄) and concentrated in vacuo. The residuewas chromatographed on silicagel in heptane/ethyl acetate=1/0=>0/1 (v/v)as eluent.

Yield: 28 mg. MS-ESI: [M+H]⁺=551.4; HPLC: R_(t)=3.75 min. (method 2)

Example 121-Acetyl-4-phenyl-6-(4-phenylbenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(11 mg) with 4-biphenylcarbonyl chloride (16 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 6.

Yield: 1.0 mg. MS-ESI: [M+H]⁺=489.4; HPLC: R_(t)=11.62 min. (method 1)

Example 131-Acetyl-6-(4-[4-chlorophenyl]benzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a).1-Acetyl-6-(4-iodobenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

A mixture of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(300 mg), 4-iodobenzoyl chloride (520 mg) and a catalytic amount ofN,N-dimethylaminopyridine in pyridine (4 ml) was stirred for 18 h. Thereaction mixture was concentrated in vacuo, the residue was dissolved inethyl acetate and washed with saturated aq. NaHCO₃, water and brine. Theorganic layer was dried (MgSO₄) and concentrated in vacuo.

Yield: 460 mg. MS-ESI: [M+H]⁺=539.4; HPLC: R_(t)=10.98 min. (method 1)

(b).1-Acetyl-6-(4-[4-chlorophenyl]benzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

A mixture of1-acetyl-6-(4-iodobenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(25 mg), 4-chlorobenzeneboronic acid (22 mg), cesium fluoride (14 mg),triphenylphosphine (5.0 mg) and tris(dibenzylideneacetone)dipalladium(0)(4.3 mg) in dimethoxyethane/ethanol 4:1 (5 ml) was stirred for 15 min.as nitrogen was bubbled through the solution. After 3 h. at 80° C. thereaction mixture was concentrated in vacuo, the residue was dissolved inethyl acetate and washed with 0.5 M HCl, water, 5% aq. NaHCO₃, water andbrine. The organic layer was dried (MgSO₄) and concentrated in vacuo.The residue was chromatographed on silicagel in heptane/ethylacetate=1/0

0/1 (v/v) as eluent.

Yield: 16 mg. MS-ESI: [M+H]⁺⁼523.4; HPLC: R_(t)=4.40 min. (method 2)

Example 141-Acetyl-4-phenyl-6-(4-[3-pyridyl]benzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Suzuki cross-coupling of1-acetyl-6-(4-iodobenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(25 mg), pyridine-3-boronic acid-1,3-propanediol cyclic ester (23 mg),cesium fluoride (14 mg), triphenylphosphine (5.0 mg) andtris(dibenzylideneacetone)dipalladium(0) (4.3 mg) indimethoxyethane/ethanol 4:1 (v/v) (5 ml) was performed according to themethod described in example 13.

Yield: 17 mg. MS-ESI: [M+H]⁺=490.4; HPLC: R_(t)=7.11 min. (method 1)

Example 151-Acetyl-4-phenyl-6-(2-phenyl-5-methoxybenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a).1-Acetyl-6-(2-bromo-5-methoxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(25 mg) with 2-bromo-5-methoxybenzoic acid (21 mg) under the agency ofHATU (68 mg) and N,N-diisopropylethylamine (32 μl) in dichloromethane (4ml) was performed according to the method described in example 11.

Yield: 31 mg. MS-ESI: [M+H]⁺=521.4; HPLC: R_(t)=3.74 min. (method 2)

(b).1-Acetyl-4-phenyl-6-(2-phenyl-5-methoxybenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Suzuki cross-coupling of1-acetyl-4-phenyl-6-(2-bromo-5-methoxybenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(30 mg), benzeneboronic acid (25 mg), cesium fluoride (21 mg),triphenylphosphine (7.0 mg) and tris(dibenzylideneacetone)dipalladium(0)(6.0 mg) in dimethoxyethane/ethanol 4:1 (v/v) (5 ml) was performedaccording to the method described in example 13.

Yield: 23 mg. MS-ESI: [M+H]⁺=519.4; HPLC: R_(t)=10.87 min. (method 1)

Example 161-Acetyl-4-phenyl-6-(2-phenyl-3-methylbenzoynamino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a).1-Acetyl-4-phenyl-6-(2-bromo-3-methylbenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(25 mg) with 2-bromo-3-methylbenzoic acid (19 mg) under the agency ofHATU (68 mg) and N,N-diisopropylethylamine (32 μl) in dichloromethane (4ml) was performed according to the method described in example 11.

Yield: 16.3 mg. MS ESI: [M+H]⁺=505.2; HPLC: R_(t)=3.80 min. (method 2)

(b).1-Acetyl-4-phenyl-6-(2-phenyl-3-methylbenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Suzuki cross-coupling of1-acetyl-4-phenyl-6-(2-bromo-3-methylbenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(16 mg), benzeneboronic acid (25 mg), cesium fluoride (21 mg),triphenylphosphine (7.0 mg) and tris(dibenzylideneacetone)dipalladium(0)(6.0 mg) in dimethoxyethane/ethanol 4:1 (v/v) (5 ml) was performedaccording to the method described in example 13.

Yield: 4.9 mg. MS-ESI: [M+H]⁺=503.3; HPLC: R_(t)=4.61 min (method 2)

Example 171-Acetyl-4-phenyl-1,2,3,4-tetrahydro-6-(α-toluenesulfonyl)amino-2,2,4-trimethylquinoline

Sulfonylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with α-toluenesulfonyl chloride (12 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (25 ml) wasperformed according to the acylation method described in example 6.

Yield: 9.8 mg. MS-ESI: [M+H]⁺=463.4; HPLC: R_(t)=9.49 min. (method 1)

Example 181-Acetyl-4-phenyl-6-(phenylaminocarbonyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

A mixture of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg), phenyl isocyanate (8.0 mg) and N,N-diisopropylethylamine (22μl) in tetrahydrofuran (1 ml) was stirred for 18 h. The reaction mixturewas concentrated in vacuo, the residue was dissolved in ethyl acetateand washed with 0.5 M HCl, water, 5% aq. NaHCO₃, water and brine. Theorganic layer was dried (MgSO₄) and concentrated in vacuo. The residuewas chromatographed on silicagel in heptane/ethyl acetate=1/0

0/1 (v/v) as eluent.

Yield: 3.8 mg. MS-ESI: [M+H]⁺=428.4; HPLC: R_(t)=10.39 min. (method 1)

Example 191-Acetyl-6-(tert-butylaminothiocarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Thiourea formation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with tert-butyl isothiocyanate (7.5 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 18.

Yield: 0.50 mg. MS-ESI: [M+H]⁺=424.4; HPLC: R_(t)=5.90 min. (method 1)

Example 201-Acetyl-6-(4-tert-butylbenzyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline.trifluoroaceticacid

A mixture of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg), 4-(tert-butyl)benzylchloride (6.5 mg) andN,N-diisopropylethylamine (10 μl) in tetrahydrofuran (1 ml) was stirredat 50° C. for 18 h. The reaction mixture was concentrated in vacuo, theresidue was dissolved in ethyl acetate and washed with 0.5 HCl, water,5% aq. NaHCO₃, water and brine. The organic layer was dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed on silicagel inheptane/ethyl acetate=1/0

0/1 (v/v) as eluent.

Yield: 3.1 mg. MS-ESI: [M+H]⁺=455.4; HPLC: R_(t)=10.00 min. (method 1)

Example 211-Acetyl-4-phenyl-6-(3-phenylpropionyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 3-phenylpropionyl chloride (11 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 6.

Yield: 1.2 mg. MS-ESI: [M+H]⁺=441.4; HPLC: R_(t)=10.25 min. (method 1)

Example 221-Acetyl-6-(2-furoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 2-furoyl chloride (8.5 mg) and N,N-diisopropylethylamine(22 μl) in tetrahydrofuran (1 ml) was performed according to the methoddescribed in example 6.

Yield: 7.7 mg. MS-ESI: [M+H]⁺=403.4; HPLC: R_(t)=8.91 min. (method 1)

Example 231-Acetyl-6-(isovaleryl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with isovaleryl chloride (7.8 mg) and N,N-diisopropylethylamine(22 μl) in tetrahydrofuran (1 ml) was performed according to the methoddescribed in example 6.

Yield: 5.3 mg. MS-ESI: [M+H]⁺=393.4; HPLC: R_(t)=9.35 min (method 1)

Example 241-Acetyl-6-(3-[adamantan-1-yl]propionyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 3-(adamantan-1-yl)propionic acid (10 mg) under the agencyof HATU (25 mg) and N,N-diisopropylethylamine (22 μl) in dichloromethane(1 ml) was performed according to the method described in example 11.

Yield: 6.7 mg. MS-ESI: [M+H]⁺=499.4; HPLC: R_(t)=12.43 min. (method 1)

Example 25 1-Acetyl-6-(ethylmalonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(150 mg) with ethyl malonyl chloride (147 mg) andN,N-diisopropylethylamine (314 μl) in tetrahydrofuran (8 ml) wasperformed according to the method described in example 6.

Yield: 163 mg. MS-ESI: [M+H]⁺=423.2; HPLC: R_(t)=8.48 min. (method 1)

Example 261-Acetyl-6-([4-methoxybenzylamino]carbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a).1-Acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

A 2 M NaOH solution was added dropwise to a stirred solution of1-acetyl-6-(ethylmalonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (161mg) in dioxane/water 4:1 (v/v) (12 ml) until pH 14. After stirring for3.5 h, the reaction mixture was poured into water and extracted withethyl acetate at pH 2. The organic layer was washed with water andbrine, dried (MgSO₄) and concentrated in vacuo.

Yield: 163 mg. MS-ESI: [M+H]⁺=395.2; HPLC: R_(t)=7.43 min. (method 1)

(b).1-Acetyl-6-([4-methoxybenzylamino]carbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of 4-methoxybenzylamine (5.2 mg) with1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg), under the agency of HATU (19 mg) and N,N-diisopropylethylamine(16 μl) in tetrahydrofuran (2 ml) was performed according to the methoddescribed in example 11.

Yield: 7.3 mg. MS-ESI: [M+H]⁺=514.4; HPLC: R_(t)=8.80 min. (method 1)

Example 271-Acetyl-6-[ethoxycarbonylmethylamino]carbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of glycine ethyl ester.HCl (5.3 mg) with1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg), under the agency of HATU (19 mg) and N,N-diisopropylethylamine(16 μl) in tetrahydrofuran (2 ml) was performed according to the methoddescribed in example 11.

Yield: 4.6 mg. MS-ESI: [M+H]⁺=480.6; HPLC: R_(t)=7.94 min (method 1)

Example 281-Acetyl-6-([N-ethyl-N-benzylamino]carbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of N-ethylbenzylamine (5.2 mg) with1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg), under the agency of HATU (19 mg) and N,N-diisopropylethylamine(16 μl) in tetrahydrofuran (2 ml) was performed according to the methoddescribed in example 11.

Yield: 7.3 mg. MS-ESI: [M+H]⁺=512.6; HPLC: R_(t)=9.36 min. (method 1)

Example 291-Acetyl-6-([2,4-difluorobenzylamino]methylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a).1-Acetyl-6-(bromoacetyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(130 mg) with bromoacetyl chloride (69 μl) and N,N-diisopropylethylamine(121 μl) in dichloromethane (10 ml) was performed according to themethod described in example 6.

Yield: 151 mg. MS-ESI: [M+H]⁺=431.2

(b).1-Acetyl-6-([2,4-difluorobenzylamino]methylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

A mixture of1-acetyl-6-(bromoacetyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg), 2,4-difluorobenzylamine (6.0 mg) and N,N-diisopropylethylamine(10 μl) in dioxane (2 ml) was stirred at 40° C. for 18 h. The reactionmixture was concentrated in vacuo. The residue was chromatographed onsilicagel in dichloromethane/methanol=1/0

95/5 (v/v) as eluent.

Yield: 5.5 mg. MS-ESI: [M+H]⁺=492.4; HPLC: R_(t)=6.74 min. (method 1)

Example 301-Acetyl-6-([4-{1-phenyl}-piperazinyl]methylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

N-Alkylation of 1-phenylpiperazine (7.0 μl) with1-acetyl-6-(bromoacetyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) and N,N-diisopropylethylamine (10 μl) in dioxane (2 ml) wasperformed according to the method described in example 29.

Yield: 8.4 mg. MS-ESI: [M+H]⁺=511.4; HPLC: R_(t)=7.01 min. (method 1)

Example 311-Acetyl-6-([N-morpholino]methylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

N-Alkylation of morpholine (4.0 μl) with1-acetyl-6-(bromoacetyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) and N,N-diisopropylethylamine (9.0 μl) in dichloromethane (2 ml)was performed according to the method described in example 29.

Yield: 10 mg. MS-ESI: [M+H]⁺=436.4; HPLC: R_(t)=5.64 min. (method 1)

Example 321-Acetyl-6-(2-thiophenemethylamino)carbonyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a). 1,2-dihydro-2,2,4-trimethylquinoline-6-carboxylic acid methyl ester

Skraup reaction of methyl 4-aminobenzoate (5.0 g) and iodine (1.7 g) inmesityl oxide (25 ml) was performed according to the method described inexample 1.

Yield: 2.3 g. MS-ESI: [M+H]⁺=232.2

(b). 1-Acetyl-1,2-dihydro-2,2,4-trimethylquinoline-6-carboxylic acidmethyl ester

A mixture of 1,2-dihydro-2,2,4-trimethylquinoline-6-carboxylic acidmethyl ester (2.3 g) and a catalytic amount of N,N-dimethylaminopyridinein acetic anhydride (60 ml) was stirred at 100° C. for 18 h. Thereaction mixture was concentrated in vacuo, the residue was dissolved inethyl acetate and washed with water and brine. The organic layer wasdried (MgSO₄) and concentrated in vacuo. The residue was chromatographedon silicagel in heptane/ethyl acetate=1/1

1/9 (v/v) as eluent.

Yield: 2.3 g.

(c).1-Acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylicacid methyl ester

Friedel-Crafts alkylation of benzene (60 ml) with1-acetyl-1,2-dihydro-2,2,4-trimethylquinoline-6-carboxylic acid methylester (2.3 g) in the presence of AlCl₃ (4.4 g) was performed accordingto the method described in example 3.

Yield: 1.2 g. MS-ESI: [M+H]⁺=352.4; HPLC: R_(t)=9.72 min. (method 1)

(d).1-Acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylicacid

A 2 M NaOH solution was added dropwise to a stirred solution of1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylicacid methyl ester (1.2 g) in dioxane/water 4:1 (v/v) (50 ml) until pH12. After stirring for 18 h, the reaction mixture was poured into waterand extracted with ethyl acetate at pH 2. The organic layer was washedwith water and brine, dried (MgSO₄) and concentrated in vacuo.

Yield: 891 mg. MS-ESI: [M+H]⁺=338.2

(e).1-Acetyl-6-(2-thiophenemethylamino)carbonyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of 2-thiophenemethylamine (5.0 mg) with1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylicacid (10 mg), under the agency of HATU (23 mg) andN,N-diisopropylethylamine (19 μl) in dichloromethane (2 ml) wasperformed according to the method described in example 11.

Yield: 3.0 mg. MS-ESI: [M+H]⁺=433.4; HPLC: R_(t)=9.28 min. (method 1)

Example 331-Acetyl-6-(2-[4-methoxyphenyl]ethylamino)carbonyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of 2-(4-methoxyphenyl)ethylamine (6.1 mg) with1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylicacid (10 mg), under the agency of HATU (23 mg) andN,N-diisopropylethylamine (19 μl)) in dichloromethane (2 ml) wasperformed according to the method described in example 11.

Yield: 9.9 mg. MS-ESI: [M+H]⁺=457.4; HPLC: R_(t)=9.34 min. (method 1)

Example 341-Acetyl-6-(3-isopropoxypropylamino)carbonyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of 3-isopropoxypropylamine (5.2 mg) with1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylicacid (10 mg), under the agency of HATU (23 mg) andN,N-diisopropylethylamine (19 μl) in dichloromethane (2 ml) wasperformed according to the method described in example 11.

Yield: 8.8 mg. MS-ESI: [M+H]⁺=437.4; HPLC: R_(t)=8.80 min. (method 1)

Example 351-Acetyl-6-(2-[methylthio]ethylamino)carbonyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of 2-(methylthio)ethylamine (4.1 mg) with1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylicacid (10 mg), under the agency of HATU (23 mg) andN,N-diisopropylethylamine (19 μl) in dichloromethane (2 ml) wasperformed according to the method described in example 11.

Yield: 10 mg. MS-ESI: [M+H]⁺=411.4; HPLC: R_(t)=3.33 min (method 2)

Example 361-Acetyl-6-(4-methoxybenzyloxy)carbonyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of 4-methoxybenzylalcohol (6.2 mg) with1-acetyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline-6-carboxylicacid (10 mg), under the agency of HATU (23 mg) andN,N-diisopropylethylamine (19 μl) in dichloromethane (2 ml) wasperformed according to the method described in example 11.

Yield: 7.2 mg. MS-ESI: [M+H]⁺=458.4; HPLC: R_(t)=3.90 min. (method 2)

Example 371-Acetyl-6-(4-phenylbenzoyl)oxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a). 1,2-Dihydro-6-methoxy-2,2,4-trimethylquinoline

Skraup reaction of 4-anisidine (5.0 g) and iodine (1.7 g) in mesityloxide (25 ml) was performed according to the method described in example1.

Yield: 2.3 g. MS-ESI: [M+H]⁺=204.2

(b). 1-Acetyl-1,2-dihydro-6-methoxy-2,2,4-trimethylquinoline

Acetyl chloride (8 ml) was added dropwise to a cooled (0° C.) solutionof 1,2-dihydro-6-methoxy-2,2,4-trimethylquinoline (1.7 g) and acatalytic amount of N,N-dimethylaminopyridine in pyridine (60 ml). Afterstirring for 18 h, the reaction mixture was concentrated in vacuo. Theresidue was dissolved in dichloromethane and washed with 1 M HCl, water,5% aq. NaHCO₃, water and brine. The organic layer was dried (MgSO₄) andconcentrated in vacuo. The residue was chromatographed on silicagel indichloromethane as eluent.

Yield: 1.8 g. MS-ESI: [M+H]⁺=246.2

(c).1-Acetyl-6-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Fiedel-Crafts alkylation of benzene (25 ml) with1-acetyl-1,2-dihydro-6-methoxy-2,2,4-trimethylquinioline (1.8 g) in thepresence of AlCl₃ (3.0 g) was performed according to the methoddescribed in example 3.

Yield: 1.9 g. HPLC: R_(t)=9.62 min. (method 1)

(d).1-Acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Boron tribromide (1.30 ml) was added dropwise to a cooled (0° C.)solution of1-acetyl-6-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(0.9 g) in dichloromethane (75 ml). After stirring for 18 h, thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was washed with water, 5% aq. NaHCO₃ and water, dried(MgSO₄) and concentrated in vacuo.

Yield: 950 mg. MS-ESI: [M+H]⁺=310.2; HPLC: R_(t)=8.41 min. (method 1)

(e).1-Acetyl-4-phenyl-6-(4-phenylbenzoyl)oxy-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 4-biphenylcarbonyl chloride (14 mg) andN,N-diisopropylethylamine (28 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 6.

Yield: 8.2 mg. MS-ESI: [M+H]⁺=490.4; HPLC: R_(t)=12.81 min. (method 1)

Example 381-Acetyl-6-(tert-butylacetyl)oxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with tert-butylacetyl chloride (9.0 μl) andN,N-diisopropylethylamine (28 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 6.

Yield: 3.9 mg. MS-ESI: [M+H]⁺=408.4; HPLC: R_(t)=11.28 min. (method 1)

Example 391-Acetyl-6-(cyclopropylmethyl)oxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

A mixture of1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(20 mg), cesium carbonate (63 mg), tetrabutylammonium bromide (29 mg)and chloromethylcyclopropane (8.4 μl) in acetonitrile (1 ml) was stirredat 50° C. for 18 h. The reaction mixture was concentrated in vacuo andthe residue was chromatographed on silicagel in heptane/ethylacetate=1/0

6/4 (v/v) as eluent.

Yield: 10 mg. MS-ESI: [M+H]⁺=364.2; HPLC: R_(t)=10.73 min. (method 1)

Example 401-Acetyl-6-(3-pyridylmethyl)oxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Alkylation of1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(20 mg) with 3-picolylchloride.HCl (12 mg), cesium carbonate (63 mg) andtetrabutylammonium bromide (30 mg) acetonitrile (1 ml) was performedaccording to the method described in example 39.

Yield: 10 mg: MS-ESI: [M+H]⁺=401.2; HPLC: R_(t)=8.40 min. (method 1)

Example 411-Acetyl-6-ethyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a). 1,2-Dihydro-6-ethyl-2,2,4-trimethylquinoline

Skraup reaction of p-ethylaniline (1.0 g) and iodine (0.34 g) in mesityloxide (5 ml) was performed according to the method described in example1.

Yield: 800 mg. MS-ESI: [M+H]⁺=202.2

(b). 1-Acetyl-6-ethyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of 1,2-dihydro-6-ethyl-2,2,4-trimethylquinoline (800 mg) withacetyl chloride (3.5 ml) and a catalytic amount ofN,N-dimethylaminopyridine in pyridine (25 ml) was performed according tothe method described in example 37.

Yield: 410 mg. MS-ESI: [M+H]⁺=244.2

(c).1-Acetyl-6-ethyl-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Friedel-Crafts alkylation of benzene (10 ml) with1-acetyl-6-ethyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (410 mg) inthe presence of AlCl₃ (710 mg) was performed according to the methoddescribed in example 3.

Yield: 407 mg. MS-ESI: [M+H]⁺=322.4

Example 421-Acetyl-6-(1,1′-biphenyl)-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a).1-Acetyl-6-iodo-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

A sodium nitrite solution (31 mg) was added dropwise to a cooled (0° C.)solution of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(128 mg) and sulfuric acid (82 mg) in water (2 ml). After stirring at 0°C. for 15 min, a potassium iodide solution (105 mg) was added. Afterstirring for 18 h, the reaction mixture was poured into dichloromethane.The organic layer was separated and washed with 5% aq. sodiumthiosulfate and water, dried (MgSO₄) and concentrated in vacuo.

Yield: 160 mg. MS-ESI: [M+H]⁺=420.0

(b).1-Acetyl-6-(1,1′-biphenyl-yl)-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Suzuki cross-coupling of1-acetyl-6-iodo-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20mg), (1,1′-biphenyl-4-yl)boronic acid (28 mg), cesium fluoride (15 mg),triphenylphosphine (5 mg) and tris(dibenzylideneacetone)dipalladium(0)(4.5 mg) in dimethoxyethane/ethanol 4:1 (v/v) (5 ml) was performedaccording to the method described in example 13.

Yield: 16 mg. MS-ESI: [M+H]⁺=446.4; HPLC: R_(t)=6.84 min. (method 2)

Example 431-Acetyl-6-(4-chlorophenyl)-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Suzuki cross-coupling of1-acetyl-6-iodo-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20mg), 4-chlorophenylboronic acid (22 mg), cesium fluoride (15 mg),triphenylphosphine (5 mg) and tris(dibenzylideneacetone)dipalladium(0)(4.5 mg) in dimethoxyethane/ethanol 4:1 (v/v) (5 ml) was performedaccording to the method described in example 13.

Yield: 8.6 mg. MS-ESI: [M+H]⁺=404.4; HPLC: R_(t)=5.94 min. (method 2)

Example 441-Acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4,7-tetramethylquinoline(a). 1-Acetyl-6-amino-1,2-dihydro-2,2,4,7-tetramethylquinoline

A mixture of N-Boc-2-methyl-1,4-phenylenediamine (2.3 g), magnesiumsulfate (6.3 g), 4-tert-butylcatechol (100 mg) and iodine (300 mg) inacetone (15 ml) was stirred at reflux for 20 h. The reaction mixture wascooled to r.t. and filtered. The filtrate was concentrated in vacuo andthe residue was chromatographed on SiO₂ with heptane/ethyl acetate=1/0

3/1 (v/v) as eluent. The product,6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4,7-tetramethylquinoline,was acylated with acetyl chloride (1.0 ml) in a mixture of pyridine (1.0ml) and toluene (10 ml). After stirring for 1 h, the reaction mixturewas washed with 3% aq. citric acid and water. The organic layer wasdried (MgSO₄) and concentrated in vacuo. The residue was chromatographedon silicagel in heptane/ethyl acetate=1/0

3/1 (v/v) as eluent.

Yield: 350 mg. MS-ESI: [M+H]⁺=345.4

(b).1-Acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4,7-tetramethylquinoline

AlCl₃ (266 mg) was added to a heated (70° C.) solution of1-acetyl-6-amino-1,2-dihydro-2,2,4,7-tetramethylquinoline (100 mg) inbenzene (10 ml). After 3 h, the mixture was cooled and concentrated invacuo. The residue was dissolved in ethyl acetate and washed with water.The organic layer was separated, dried (MgSO₄) and concentrated invacuo. The residue was chromatographed on silicagel in heptane/ethylacetate=1/0

3/1 (v/v) as eluent.

Yield: 75 mg. MS-ESI: [M+H]⁺=323.4

Example 451-Acetyl-6-(4-phenylbenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4,7-tetramethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4,7-tetramethylquinoline(20 mg) with 4-biphenylcarbonyl chloride (100 mg) and pyridine (100 l)in tetrahydrofuran (5 ml) was performed according to the methoddescribed in example 6.

Yield: 24 mg. MS-ESI: [M+H]⁺=503.4

Example 461-Acetyl-6-(4-phenylbenzoyl)amino-8-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a).1-Acetyl-6-amino-8-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Skraup reaction of N-Boc-3-methoxy-1,4-phenylenediamine (450 mg),magnesium sulfate (1.0 g), 4-tert-butylcatachol (10 mg) and iodine (20mg) in acetone (10 ml), acylation of the product with acetyl chloride(250 μl) and pyridine (250 ml) in toluene (10 ml) and subsequentFriedel-Crafts alkylation with AlCl₃ (266 mg) were performed accordingto the methods discribed in example 44.

Yield: 71 mg. MS-ESI: [M+H]⁺=339.4

(b).1-Acetyl-6-(4-phenylbenzoyl)amino-8-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-8-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(20 mg) with 4-biphenylcarbonyl chloride (100 mg) and pyridine (100 μl)in tetrahydrofuran (5 ml) was performed according to the methoddescribed in example 6.

Yield: 25 mg. MS-ESI: [M+H]⁺=519.4

Example 471-Acetyl-6-(2-furoyl)amino-1,2,3,4-tetrahydro-4-toloyl-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-toloyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 2-furoyl chloride (8.1 mg) and N,N-diisopropylethylamine(20 μl) in tetrahydrofuran (1 ml) was performed according to the methoddescribed in example 6.

Yield: 12 mg. MS-ESI: [M+H]⁺=417.4; HPLC: R_(t)=4.90 min. (method 2)

Example 481-Acetyl-6-(4-phenylbenzoyl)amino-1,2,3,4-tetrahydro-4-toloyl-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-toloyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 4-biphenylcarbonyl chloride (14 mg) andN,N-diisopropylethylamine (20 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 6.

Yield: 9.3 mg. MS-ESI: [M+H]⁺=503.4; HPLC: R_(t)=6.08 min (method 2)

Example 49 1-Acetyl-6-(ethylmalonyl)amino-1,2,3,4-tetrahydro-4-toloyl-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-toloyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with ethyl malonyl chloride (9.4 mg) andN,N-diisopropylethylamine (20 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 6.

Yield: 12 mg. MS-ESI: [M+H]⁺=437.4; HPLC: R_(t)=4.71 min. (method 2)

Example 501-Acetyl-6-(3,5-dibromobenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

HATU condensation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 3,5-dibromobenzoic acid (10 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 11.

Yield: 15.9 mg. MS-ESI: [M+H]⁺=470.9; HPLC: R_(t)=10.11 min. (method 1)

Example 511-Acetyl-6-(5-bromo-2-methylaminobenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

HATU condensation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 5-bromo-2-methylaminobenzoic acid (8.4 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 11.

Yield: 13.2 mg. MS-ESI: [M+H]⁺=522.1; HPLC: R_(t)=8.95 min. (method 1)

Example 521-Acetyl-6-(3,4,5-trimethoxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 3,4,5-trimethoxybenzoyl chloride (12 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 6.

Yield: 14.5 mg. MS-ESI: [M+H]⁺=503.2; HPLC: R_(t)=11.26 min. (method 1)

Example 531-Acetyl-6-(3,5-dichloro-2,6-dimethoxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

HATU condensation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 3,5-dichloro-2,6-dimethoxybenzoic acid (9.0 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 11.

Yield: 15.1 mg. MS-ESI: [M+H]⁺=541.1; HPLC: R_(t)=10.92 min. (method 1)

Example 541-Acetyl-6-(2-acetyloxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

HATU condensation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 2-acetyloxybenzoic acid (6.0 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 11.

Yield: 1.1 mg. MS-ESI: [M+H]⁺=471.2; HPLC: R_(t)=14.35 min. (method 1)

Example 551-Acetyl-6-(2-acetamido-5-bromobenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

HATU condensation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 2-acetamido-5-bromobenzoic acid (6.0 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 11.

Yield: 2.3 mg. MS-ESI: [M+H]⁺=530.2; HPLC: R_(t)=12.01 min. (method 1)

Example 561-Acetyl-6-(5-bromo-2-N,N-dimethylcarbamoylbenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

HATU condensation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 5-bromosalicylic acid (8.0 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 11.

Yield: 3.0 mg. MS-ESI: [M+H]⁺=580.2; HPLC: R_(t)=12.53 min. (method 1)

Example 571-Acetyl-6-(2-[4-toloyloxy]benzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

HATU condensation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) with 2-[4-toloyloxy]benzoic acid (8.0 mg) andN,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 11.

Yield: 8.0 mg. MS-ESI: [M+H]⁺=519.4; HPLC: R_(t)=13.11 min. (method 1)

Example 581-Acetyl-6-(2-methylsulfonyloxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a).1-Acetyl-6-(2-methoxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(0.60 g) with 2-methoxybenzoyl chloride (1.0 g) andN,N-diisopropylethylamine (1.7 ml) in tetrahydrofuran (60 ml) wasperformed according to the method described in example 6.

Yield: 0.65 g. MS-ESI: [M+H]⁺=443.4

(b).1-Acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

BBr₃ (0.69 ml) was added dropwise to a solution of1-acetyl-6-(2-methoxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(0.64 g) in dichloromethane (40 mL). After stirring for 4 h, TLCindicated complete conversion. Water was added to the reaction mixtureand stirring was continued for 15 min. The mixture was washed with 5%aq. NaHCO₃ and water. The organic layer was dried (MgSO₄) andconcentrated in vacuo. The resulting product was used without furtherpurification.

Yield: 0.62 g. MS-ESI: [M+H]⁺=429.4

(c).1-Acetyl-6-(2-methylsulfonyloxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Sulfonylation of1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(12 mg) with methylsulfonyl chloride (6.5 μl) was performed in pyridine(1 ml). TLC analysis after stirring for 16 h showed conversion to ahigher-running product. The mixture was concentrated, the residue wasdissolved in dichloromethane and washed with water. The organic layerwas dried (Na₂SO₄) and concentrated in vacuo. The crude product waspurified by silica gel column chromatography. Eluent: heptane/ethylacetate=8/2 (v/v).

Yield: 8.0 mg. MS-ESI: [M+H]⁺=507.4; HPLC: R_(t)=5.03 min. (method 2)

Example 591-Acetyl-6-(2-[3,5-dimethylisoxazole-4-sulfonyl]oxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Sulfonylation of1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(20 mg) with 3,5-dimethylisoxazole-4-sulfonyl chloride (27 mg) inpyridine (2 ml) was performed according to the method described inexample 58.

Yield: 14 mg. MS-ESI: [M+H]⁺=588.4; HPLC: R_(t)=14.46 min. (method 1)

Example 601-Acetyl-6-(2-methoxycarbonylethylcarbonyloxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(20 mg) with 3-carbomethoxypropiolnyl chloride (14 mg) andN,N-diisopropylethylamine (40 μl) in tetrahydrofuran (2 ml) wasperformed according to the method described in example 6.

Yield: 21.4 mg. MS-ESI: [M+H]⁺=543.6; HPLC: R_(t)=6.98 min. (method 1)

Example 611-Acetyl-6-(2-[5-methylisoxazole-3-carbonyl]oxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(15 mg) with 5-methylisoxazole-3-carbonyl chloride (10 mg) andN,N-diisopropylethylamine (30 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 6.

Yield: 4.0 mg. MS-ESI: [M+H]⁺=538.4; HPLC: R_(t)=9.84 min. (method 1)

Example 621-Acetyl-6-(2-[2-oxazolidinone-5-methyl]oxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Alkylation of1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(20 mg) with 5-chloromethyl-2-oxazolidinone (7 mg), cesium carbonate (63mg) and tetrabutylammonium bromide (30 mg) in acetonitrile (1 ml) wasperformed according to the method described in example 39.

Yield: 25 mg. MS-ESI: [M+H]⁺=542.4; HPLC: R_(t)=8.21 min. (method 1)

Example 631-Acetyl-6-(2-[morpholino-4-carbonyl]oxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-(2-hydroxybenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(15 mg) with morpholino-4-carbonyl chloride (12 μl) andN,N-diisopropylethylamine (30 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 6.

Yield: 5.4 mg. MS-ESI: [M+H]⁺=542.4; HPLC: R_(t)=10.02 min. (method 1)

Example 641-Acetyl-6-(2-phenylaminobenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

HATU condensation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(15 mg) with N-phenylanthranilic acid (21 mg) andN,N-diisopropylethylamine (33 μl) in tetrahydrofuran (1 ml) wasperformed according to the method described in example 11.

Yield: 5.8 mg. MS-ESI: [M+H]⁺=504.4; HPLC: R_(t)=13.42 min. (method 1)

Example 651-Acetyl-6-(2-pyrrolidone-N-ethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a).1-Acetyl-6-acryloylamino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Acylation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(0.12 g) with acryloyl chloride (39 μl) and N,N-diisopropylethylamine(0.21 ml) in tetrahydrofuran (10 ml) was performed according to themethod described in example 6.

Yield: 0.13 g. MS-ESI: [M+H]⁺=363.2

(b).1-Acetyl-6-(2-pyrrolidone-N-ethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

To a mixture of 2-pyrrolidone (19 mg) and NaH (18 mg, 60% in oil) in TBF(1 mL) was added1-acetyl-6-acryloylamino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(8 mg) in THF (1 mL). After stirring for 18 h, TLC analysis indicatedconversion into a higher-running product. The mixture was diluted withethyl acetate and washed with water, 0.5 N HCl and water. The organiclayer was dried (Na₂SO₄) and concentrated in vacuo. Purification wasaccomplished by silica gel column chromatography, using heptane/ethylacetate=8/2

1/1 (v/v) as eluent.

Yield: 4.6 mg. MS-ESI: [M+H]⁺=448.4; HPLC: R_(t)=4.51 min. (method 2)

Example 661-Acetyl-6-(ethoxyethoxyethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Michael addition of 2-ethoxyethanol (19 mg) and1-acetyl-6-acryloylamino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(8 mg) in THF (1 mL) was performed according to the method described inexample 65.

Yield: 1.0 mg. MS-ESI: [M+H]⁺=453.4; HPLC: R_(t)=5.03 min. (method 2)

Example 671-Acetyl-6-(2-pyrrolidone-N-methoxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of N-hydroxymethyl-2-pyrrolidone (22 mg) and1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(15 mg) under the agency of HATU (29 mg) and N,N-diisopropylethylamine(33 μl) in tetrahydrofuran (2 ml) was performed according to the methoddescribed in example 11.

Yield: 4.6 mg. MS-ESI: [M+H]⁺=478.4; HPLC: R_(t)=5.53 min. (method 2)

Example 681-Acetyl-6-(tert-butylcarbamoyl-N-[2-ethoxy]carbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of tert-butyl-N-(2-hydroxyethyl)carbamate (29 μl) and1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(15 mg) under the agency of HATU (29 mg) and N,N-diisopropylethylamine(33 μl) in tetrahydrofuran (2 ml) was performed according to the methoddescribed in example 11.

Yield: 11 mg. MS-ESI: [M+H]⁺=538.4; HPLC: R_(t)=5.32 min. (method 2)

Example 691-Acetyl-6-(2-furylmethoxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of furfuryl alcohol (17 μl) and1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(15 mg) under the agency of HATU (29 mg) and N,N-diisopropylethylamine(33 μl) in tetrahydrofuran (2 ml) was performed according to the methoddescribed in example 11.

Yield: 7.1 mg. MS-ESI: [M+H]⁺=475.4; HPLC: R_(t)=5.30 min. (method 2)

Example 701-Acetyl-6-([cyclopropylmethylaminomethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Alkylation of cyclopropylmethylamine (4 μl) with1-acetyl-6-(bromoacetyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(10 mg) and N,N-diisopropylethylamine (13 ml) in dichloromethane (1 ml)was performed according to the method described in example 29.

Yield: 6.8 mg. MS-ESI: [M+H]⁺=535.6; HPLC: R_(t)=6.29 min. (method 2)

Example 711-Acetyl-4-(2-methoxyphenyl)-6-(4-phenylbenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(a).1-Acetyl-6-(4-phenylbenzoyl)amino-1,2-dihydro-2,2,4-trimethylquinoline

1-Acetyl-6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline(1.0 g) was dissolved in a mixture of trifluoroacetic acid/CH₂Cl₂ (1/1,v/v, 25 ml) and stirred for 2 h. The reaction mixture was concentratedin vacuo, diluted with ethyl acetate and washed with 5% aq. NaHCO₃. Theorganic layer was separated, dried (MgSO₄) and concentrated. The residuewas dissolved in CH₂Cl₂ (25 ml), N,N-diisopropylethylamine (5.2 ml) and4-phenylbenzoyl chloride (2.0 g) were added and the mixture was stirredfor 16 h. The mixture was concentrated and chromatographed on silicagelin heptane/ethyl acetate=1/0

0/1 (v/v) as eluent.

Yield: 0.63 g. MS-ESI: [M+H]⁺=411.2

(b).1-Acetyl-4-(2-methoxyphenyl)-6-(4-phenylbenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinolineand1-acetyl-4-(4-methoxyphenyl)-6-(4-phenylbenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Friedel-Crafts alkylation of anisole (25 ml, stored on molecular sieves3 Å) with1-acetyl-6-(4-phenylbenzoyl)amino-1,2-dihydro-2,2,4-trimethylquinoline(0.50 g) in the presence of AlCl₃ (0.50 g) was performed according tothe method described in example 3. Purification by silica gelchromatography (eluent: heptane/ethyl acetate=1/0

0/1, v,v) yielded the 2-methoxyphenyl-substituted derivative as minorproduct and the 4-methoxyphenyl-substituted derivative as the majorproduct.

Yield: 46 mg. MS-ESI: [M+H]⁺=518.0 (2-methoxyphenyl)

Yield: 0.20 g. MS-ESI: [M+H]⁺=518.1 (4-methoxyphenyl)

Example 721-Acetyl-4-(4-hydroxyphenyl)-6-(4-phenylbenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

To a cooled (0° C.) solution of1-acetyl-4-(4-methoxyphenyl)-6-(4-phenylbenzoyl)amino-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(0.46 g) in CH₂Cl₂ was added BBr₃ under a nitrogen atmosphere. Completeconversion was reached after stirring for 3 h at room temperature. Themixture was cooled, 1 M NaOH was added until basic pH, subsequentlyethyl acetate was added and the mixture was acidified with 1 M HCl. Theorganic layer was separated, dried (MgSO₄) and concentrated. The residuewas chromatographed on silicagel in heptane/ethyl acetate=1/0→0/1 (v/v)as eluent.

Yield: 0.13 g. MS-ESI: [M+H]⁺=504.0

Example 731-Acetyl-6-(5-methylnicotinoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline

Condensation of1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline(0.10 g) with 5-methyl nicotinic acid (0.13 g) under the agency of HATU(0.18 g) and N,N-diisopropylethylamine (0.28 ml) in dichloromethane (2ml) was performed according to the method described in example 11.

Yield: 0.12 g. MS-ESI: [M+H]⁺=427.0

Example 74 CHO-FSH In Vitro Bioactivity

FSH activity of compounds were tested in Chinese Hamster Ovary (CHO)cells stably transfected with the human FSH receptor and cotransfectedwith a cAMP responsive element (CRE)/promotor directing the expressionof a firefly luciferase reporter gene. Binding of ligand to theGs-coupled FSH receptor will result in an increase of cAMP, which inturn will induce an increased transactivation of the luciferase reporterconstruct. The luciferase signal was quantified using a luminescencecounter. For test compounds, EC₅₀ values (concentration of test compoundcausing half-maximal (50%) stimulation) were calculated. For thatpurpose the software program GraphPad PRISM, version 3.0 (GraphPadsoftware Inc., San Diego) was used.

Compounds of all examples had an activity (EC₅₀) of less than 10⁻⁵ M.The compounds of examples 1, 6-13, 15, 16, 21-24, 30, 36, 37, 45, 46,48, 50-53, 55, 57, 58, 61, 63 and 64 showed an EC₅₀ of less than 10⁻⁷ M.

1. A pharmaceutical composition, comprising an effective amount of acompound according to Formula I,

or a pharmaceutically acceptable salt thereof, wherein R¹ is(1-6C)alkylcarbonyl; R² and R³ are (1-4C)alkyl; R⁴ is phenyl, optionallysubstituted with one or more substituents selected from the grouphydroxy, halogen, (1-4C)alkyl, and (1-4C)alkoxy; R⁵ is (1-4C)alkyl; Y—Xis C(O)—O, C(O)—NH or OC(O)—NH; R⁶ is (1-6C)alkyl, 1- or2-adamantyl(1-4C)alkyl, heteroaryl selected from imidazolyl,thiadiazolyl, pyridyl, (benz)thienyl, (benzo)furyl, quinolyl,tetrahydroquinolyl, quinoxalyl, indolyl, thienyl and furyl,phenyl(1-4C)alkyl, (1-4C)alkylheteroaryl, wherein the heteroaryl isselected from imidazolyl, thiadiazolyl, pyridyl, (benz)thienyl,(benzo)furyl, quinolyl, tetrahydroquinolyl, quinoxalyl, indolyl, thienyland furyl, heterocycloalkyl(1-4C)alkyl, wherein the heterocycloalkyl isselected from piperidine, morpholine and pyrrolidine,R⁸,R⁹-aminocarbonyl(1-4C)alkyl, R⁸,R⁹-amino(1-4C)alkyl,R⁸-oxycarbonyl(1-4C)alkyl, R⁸-oxy(1-4C)alkyl or phenyl, wherein phenylis optionally substituted with nitro, trifluoromethyl, chlorophenyl,pyridyl, morpholinocarbonyloxy, isoxazolecarbonyloxy,oxazolidinoneoxycarbonyl, (1-4C)alkoxycarbonyl(1-4C)alkylcarbonyloxy,(1-4C)alkylsulfonyloxy, dimethylisoxazolesulfonyloxy, and(di)phenylamino, one or more of halogens, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)(di)alkylamino, phenyl, or (1-4C)(di)alkylcarbamoyl; R⁷ is H,(1-4C)alkyl, or (1-4C)alkoxy; R⁸ is (1-4C)alkyl, phenyl(1-4C)alkyl,heteroaryl(1-4C)alkyl, wherein the heteroaryl is selected fromimidazolyl, thiadiazolyl, pyridyl, (benz)thienyl, (benzo)furyl,quinolyl, tetrahydroquinolyl, quinoxalyl, indolyl, thienyl and furyl,(3-6C)cycloalkyl(1-4C)alkyl, heterocycloalkyl(1-4C)alkyl, wherein theheterocycloalkyl is selected from piperidine, morpholine andpyrrolidine, (1-4C)alkoxy(1-4C)alkyl, (1-4C)alkoxycarbonyl(1-4C)alkyl,t-butylcarbamoyl, benzyl optionally substituted with (1-4C)alkoxy or oneor more halogens, or R⁸ together with R⁹ may form a heterocycloalkylselected from azetidine, pyrrolidine, piperidine, piperazine,thiomorpholine and morpholine, wherein the heterocycloalkyl ring isoptionally substituted with phenyl, and R⁹ is H, or (1-4C)alkyl, and apharmaceutically acceptable auxiliary.
 2. The pharmaceutical compositionaccording to claim 1, wherein in the tetrahydroquinoline compound offormula I, Y—X is C(O)—NH.
 3. The pharmaceutical composition accordingto claim 2, wherein in the tetrahydroquinoline compound of formula I, R⁶is heteroaryl selected from imidazolyl, thiadiazolyl, pyridyl,(benz)thienyl, (benzo)furyl, quinolyl, tetrahydroquinolyl, quinoxalyl,indolyl, thienyl and furyl, phenyl(1-4C)alkyl, (1-4C)alkylheteroaryl,wherein the heteroaryl is selected from imidazolyl, thiadiazolyl,pyridyl, (benz)thienyl, (benzo)furyl, quinolyl, tetrahydroquinolyl,quinoxalyl, indolyl, thienyl and furyl, or phenyl optionally substitutedwith nitro, trifluoromethyl, chlorophenyl, pyridyl,morpholinocarbonyloxy, isoxazolecarbonyloxy, oxazolidinoneoxycarbonyl,(1-4C)alkoxycarbonyl(1-4C)alkylcarbonyloxy, (1-4C)alkylsulfonyloxy,(1-4C)alkylsulfonyloxy, dimethylisoxazolesulfonyloxy, or(di)phenylamino, one or more of halogens, (1-4C)alkyl, (1-4C)alkoxy,(1-4C)(di)alkylamino, phenyl, or (1-4C)(di)alkylcarbamoyl.